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9 Articles in Volume 10, Issue #3
Body Perception Disturbance (BPD) in CRPS
Diagnostic and Therapeutic Issues of Neuropathic Pain
Realizing the “Promise” of Pain Management and Palliative Care
Emergency Protocols for the Spinal Injectionist
Therapeutic Laser in the Management of Arthritis
Post-operative Inguinodynia from Hernia Surgery
Refractory Chronic Migraine
Taking Advantage of the Peripheral Opioid Receptor
Traumatic Brain Injury (TBI) Pain Phenomena

Traumatic Brain Injury (TBI) Pain Phenomena

The primary focus when helping TBI pain patients should involve understanding the diagnoses, recognizing pain, assisting with pain relief, and providing the opportunity to improve function.

“To my patients who have taught me invaluable caveats regarding pain management.”

Robert Foery, PhD, DABCC/TC

As a result of aggressive interventions and rehabilitation, traumatic brain injury (TBI) patients are living longer. The bad news is that TBI patients are living longer with pain. Patients and families may become frustrated due to the possibility of living with intractable pain. It is well established that pain is often left underappreciated and undertreated in cognitively-impaired patients. Common neurological complications after traumatic brain injury include pain, spasticity, and late functional decline. Pain may be acute or chronic. Pain may be musculoskeletal, neuropathic (“nerve pain”), or secondary to medical complications.

A cookbook pain management approach, particularly for persons with traumatic brain injury, is inappropriate. Individualized pain management is required. Therefore the following article provides some caveats and is supplemented by patient care experiences.


More than 90 percent of wounded soldiers—the highest survival rate in American wars—have made it off the battlefield. The increased survival rates have increased for both military and civilian TBI victims.

Because of advances in evaluation and treatment of individuals after traumatic brain injury (TBI), the number of co-morbidities has risen. With the invention of Computed Tomogram (CT) in the 1970s, diagnosing life-threatening events resulted in many saved lives and a better understanding of TBI. Because many of the brain injuries involve motor vehicle accidents and falls, concurrent bodily injury frequently accompanies the event. Some researchers estimate that the rate of posttraumatic headaches approaches 90% early on1 or 44% within six months after injury.2 Unlike what is seen objectively on sophisticated scans, pain is never clearly understood because the suffering is subjective. Objectively, one can easily comprehend pain in the presence of fractures, but even the most horrendous changes of degenerative back or neck films are not necessarily objective indications of pain. Conversely, normal spine imaging studies do not conclusively negate a patient’s pain complaints. For example, chronic myofascial pain syndromes—a significant cause of disability—is not visible on imaging studies. Whereas a full understanding of the pathology and responses to trauma is suboptimal, it is optimized in the hands of the experienced clinician. Rehabilitation physicians’ expertise is ideal for determining residual impairments and disabilities—in addition to the medical diagnoses. This information is paramount to a complete assessment and successful rehabilitation.

Incidence and Prevalence Incidence and Prevalence

Because there are a variety of pain syndromes associated with brain injury, the reported incidence and prevalence varies. The time course of onset and duration varies from case to case. Pain can appear at anytime after TBI (either in the acute stage, during recovery, or in the stable phase). In the author’s opinion, the associated suffering of TBI pain is of greater significance than solely the incidence and prevalence of pain.

Risk Factors: Who is susceptible?

Traumatic brain injury is a leading cause of death and lifelong disability in the United States. The Centers for Disease Control and Prevention has estimated that each year, approximately 1.5 million Americans survive a TBI, among whom 230,000 are hospitalized. Each year in America approximately 50,000 people die and another 80,000 to 90,000 people are left with a permanent TBI-related disability. TBI is three times more common in men. Adolescents, young adults, and the elderly are at the highest risk. The most common mechanisms of injury are motor vehicular collisions, falls, and violence.

Pathophysiology: “Doctor, How Bad Is It?”

TBI can be categorized into primary and secondary injury. Primary injury is the damage that occurs at the time of impact. Secondary injury, influenced by medical interventions, occurs because of the body’s response to the primary injury. Both primary and secondary injury can be localized or diffuse. Local injury tends to be caused by contact forces, whereas diffuse injury is more likely caused by non-contact, acceleration-deceleration, and rotational forces.

There are numerous outcome measures used to categorize the severity of brain injury but are outside the scope of this article. The reader is encouraged to become familiar with the outcome tools. Unfortunately all have limitations, but it is important to know that they exist. There is not one diagnostic tool that specifically correlates injury severity into disability prognosis. Consequently, the rehabilitation prognosis is dependent on myriad factors, including the clinician’s rehabilitation experience and the individual’s pre-injury functional status. Brain injury severity is most commonly described by the degree of impaired consciousness as defined by the Glasgow Coma Scale. This scale designates brain injury as mild, moderate, or severe on the basis of eye opening, verbal responses and observed motor movement. The Rancho Los Amigos Levels is another tool used to characterize levels of cognitive recovery. The FIM instrument is the most widely used functional status measure in rehabilitation.

Duration of loss of consciousness (LOC) is another factor used to describe brain injury severity. Mild brain injury includes any change in mental status or LOC of 30 minutes or less, whereas moderate brain injury is a change in mental status or LOC that persists greater than 30 minutes but less than six hours. Persons who have LOC for more than six hours are considered to be severe brain injury patients.

Radiographic imaging can be helpful but remains limited in predicting functional or neuropsychological outcomes. For example, patients may have marked disability and a normal MRI. Abnormal CT or MRI findings with no neurological deficits are commonly referred to as mild TBI with complications or moderate TBI. Patients with normal scans and no neurological findings are commonly designated as mild TBI. Newer neuroimaging techniques are evolving.

Interestingly, the brain injury literature describes the “mild” or “minor” traumatic brain injury group as reporting the most pain complaints.3 The highest sites of pain listed were headache, followed by neck/shoulder, back, upper limb, and lower limb pain. It is hypothesized that the moderate and severe TBI groups are underrepresented due to their communication impairments.

The author notes many similarities in caring for brain injury and chronic pain patients. Anderson, et al3 concurs with this point of view. The investigators report a list of symptoms common between these two groups. The list includes reduced attention span, perserveration, egocentricity, depression, anxiety, impaired relationships, impaired vocational capabilities, frequent medical visits, dependence, and irritability.

Acute and Chronic Pain

It is important to distinguish acute and chronic pain for prognosis and treatment.

Acute pain:

  • Often has an identifiable or immediate onset
  • Less than three months duration
  • Examples: soft tissue, ligament, or bone injury involving the spine related to a motor vehicular accident. Recovery from the acute trauma resolves with corrective procedures

Note: Non-musculoskeletal sources may cause acute pain and can be overlooked in TBI patients (e.g., myocardial infarction, bowel obstruction, gastric perforation). Also, acute pain may evolve into chronic pain.

Chronic pain:

  • Common after TBI
  • Duration greater than 3 months
  • No cure
  • Source of disability
Type of Pain Symptoms Signs
Aching, sharp, pain;
worse with activity.
Common at neck, shoulders, elbows, low back, hips, knees.
Pain worsens with palpation or joint motion.
Burning, tingling, stabbing, shooting pain. Continuous or episodic but often not related to activity. Follows nerve supply; abdominal or distal lower limb pain. Pain does not necessarily worsen with palpation or joint motion.


Traditionally, listening to the patient is the cornerstone to diagnosis. Clinical history and physical examination usually distinguish the type of pain the patient is describing. Unfortunately, the brain injury pain assessment is difficult and is often compounded by the patient’s cognitive and communication deficits. Brain injury can be the most challenging rehabilitative endeavor. Because behavioral and cognitive impairments are the most common cause of disability, pain problems present additional hurdles. The patients are generally poor historians. In addition, behavioral overlay complicates diagnosis. It may be difficult to elucidate behavioral overlay from organic pathology. Language barriers can be another confounding factor. Yet delayed diagnosis is a risk factor for chronic pain.

There are several settings where pain may arise during the course of treatment. The first is the Intensive Care Unit. The body in the coma or near-coma state can only respond in a limited number of ways. Because the presentation is autonomic or reflexic, the examiner needs to have a high index of suspicion in order to effectively treat the patient. Patients often appear agitated. Post-traumatic agitation is seen in at least one third of brain injury survivors in the early stage of recovery. Sandel and Mysiw define agitation as a subtype of delirium unique to survivors of TBI in which the survivor is in the state of post-traumatic amnesia. This involves behavioral excesses that include some combination of aggression, inability to sit still, disinhibition, and emotional lability.4 Patients may appear agitated due to pain. Before considering any intervention for an agitated patient, a thorough evaluation is necessary. In the ICU, the most obvious causes of pain are restraints, skin irritation, wounds, iatrogenic lines, and post-surgical pain. The patient may frequently fight the respirator, pull at the lines, or fidget. In order to identify the cause, a thorough evaluation and physical exam is required.

“...clinicians unfamiliar with early TBI behaviors... may respond by prescribing sedating medications. Consequently, the sedation can mask other problems such as intracranial pressure changes, subclinical seizures, and sleep deprivation. Pain is a common, but overlooked cause of agitation after TBI.”

When evaluating any condition, wide diagnostic possibilities should be considered. This is particularly true in the TBI population. All major categories of disease should be covered. The author’s approach is to initially think of what’s most dangerous to the patient. Examples include vascular, metabolic, and infectious etiologies. Vascular injuries involve sites anywhere in the body. Structures in the neck, scalp, extremities and internal organs are possible sites. Infectious sites primarily involve the lung and bladder, but any surgical site can involve superficial or deep tissue problems

Unfortunately, clinicians unfamiliar with early TBI behaviors and, in the absence of a thorough search for the incitor of the agitation, may respond by prescribing sedating medications. Consequently, the sedation can mask other problems such as intracranial pressure changes, subclinical seizures, and sleep deprivation. Pain is a common, but overlooked cause of agitation after TBI. Combined with a diminished ability to communicate or cope with pain, it is not surprising that agitation is the result.

The acute rehabilitation setting is another place where pain is commonly managed. In fact, pain must be aggressively identified and effectively treated to avoid jeopardizing the patient’s rehabilitation. Patients are actively involved with multiple therapies, and overaggressive stretching can result in various sprains and strains. The risk of injury is increased in the TBI population due to communication, cognition, and sensory impairments. Therefore, the clinician and team must remain vigilant for potential injury. The manifestation of pain may be increased combativeness or changes in the physical exam. Up to 11 % of unrecognized fractures have been reported in the rehabilitation units. Admission total body scans are a simple technique used to survey for possible fractures, and provide baseline information for development of ectopic bone ossification (also known as heterotopic ossification). Ectopic bone formation is normal bone developing in abnormal locations. This can cause significant pain and disability. The scan can identify possible sites of ectopic bone ossification four to six weeks before a plain x-ray. The skin and vascular system should be regularly inspected for the possibility of deep venous clots. TBI patients at this stage of their recovery may not be able to describe their problem. It is not unusual for ancillary health team members to notice a new limitation in extremities. Doppler scans, pulse oximetry, lung scans or specialized (spiral) CT scans are the diagnostic “gold standard.”

Spasticity is commonly seen after moderate to severe TBI. As spasticity evolves, nerve entrapments, contractures, wounds and associated pain syndromes can occur. Spasticity—not to be confused with spasms—is abnormal muscle function due to central nervous system insult. It can cause pain, weakness, dyscoordination, muscle tightness, and disability. Spasticity management requires specialized expertise. One must determine the functional implications of spasticity and generate a treatment strategy. In general, spasticity management must start with identifying the cause. This is done by a careful physical exam and laboratory work-up. Exacerbations or causes of spasticity may include anything from a pressure wound, skin rash to a subtle neuropathic (nerve) pain syndrome. Diagnostic studies such as labs, imaging or electrodiagnostics are performed based on the physical examination. Foundational treatment strategies include positioning techniques and physical therapy. A number of medications can supplement spasticity management in order to facilitate therapy. Medications can be prescribed orally, transdermally, topically or intrathecally (directly into the central nervous system). Nerve blocks, motor point blocks, and botulinum toxin injections are focal techniques used to target localized areas of spasticity. Surgical procedures can also be offered for refractory cases.

Psychiatric disorders are a relatively common complication of brain injury, both acutely and chronically. The effects of post-traumatic stress, anxiety, and depression on pain have been explored by many researchers.4 Psychiatric causes—a chronic pain risk factor—need to be considered at all times.

“There is no algorithm for migraine treatment. The choices of medication will vary for each patient depending on headache severity and comorbidities.”


Underestimating pain and initiating inappropriate treatments result in delayed rehabilitative efforts. Since treatments can result in unwanted ill-effects, they must be thoughtfully planned. The use of certain medications and treatment protocols may be contra-indicated for the TBI patient population. The author notes witnessing side-effects from a “shotgun” pain treatment approach. This occurs when clinicians generically treat the pain symptoms without identifying the pain generator. Musculoskeletal sources—the most common source of pain in persons with TBI—can lead to additional disabilities and functional loss. Chronic neuropathic pain has no known cure and requires an aggressive approach. Interventions often require a multi-disciplinary team (e.g., patient, family, caregiver, rehabilitation physician, physical therapist, recreational therapist, psychologist, etc.) Organizing an effective functioning team is the most important factor for optimal outcomes.

General Principles

  • Acknowledge the patient’s pain and suffering.
  • Provide a proactive and positive environment.
  • Identify and treat underlying or exacerbating causes (urinary issues, spasticity, nerve entrapments, depression, etc.)
  • Enhance physical and social functioning (exercise can not be overemphasized!)
  • Address psychosocial issues, such as smoking; inadequate nutrition, substance abuse.
  • Helpful physical modalities may include range-of-motion, stretching, strengthening, standing frames, ambulation, etc. Massage, TENS, cryotherapy may supplement (caution: be careful with heat in patients with altered sensation!)
  • Individualize medication choices based on myriad factors (e.g., patient’s goals and preference; lifestyle; psychosocial situation; potential drug interaction, neurological level of injury, etc.) Medications include (but not limited to) analgesics, anti-depressants, anti-epileptic (seizure medications) and spasticity agents.
  • Maintain an open mind and develop a partnership with patient and family.
  • Offer a wide array of options to patients.
  • Consider drafting a life care plan.


Due to the complexity and life-long impact of TBI, rehabilitation physicians draft life care plans to provide individualized cost-effective care. A full life care plan is an individualized plan that identifies long-term care needs for a person with a catastrophic injury or disability. The completed plan may include multiple components in the following categories:

  • 1) Medical Care. Almost all persons in need of a life care plan require ongoing specialized medical treatment and physician follow-up.
  • 2) Diagnostics. In addition to the physician visits, procedures such as x-rays, CT scans, lab tests, and MRI's are usually required to follow–up subsequent neurological or pain complaints.
  • 3) Hospitalizations. Many conditions necessitate future surgeries or other treatments that require hospitalization. As patients age, spasticity may evolve into fixed joint deformities, necessitating surgery.
  • 4) Therapy. Physical, speech, occupational, and cognitive therapy are frequent needs of a catastrophically-disabled patient with pain.
  • 5) Transportation. Specialized vans or a transportation service are a necessity for most wheelchair-bound persons.
  • 6) Home Assistance. When a person with catastrophic disabilities is able to remain in his or her home, the family will often need in-home assistance or need to place their loved one in a supervised facility during work hours or vacation periods.
  • 7) Institutional Care. Many persons with catastrophic disabilities require immediate institutional care. Even when the person is able to return home after the accident, he or she may eventually need institutional care as the caretakers age.
  • 8) Supplies. Countless individually-inexpensive commodities must be projected, including latex gloves, diapers, catheters, etc. When extended over the individual's life expectancy, the cost becomes significant.
  • 9) Other. Home modifications, specialized equipment, medication—the list goes on, with each case having different needs. Conversely, aggressive preventive care may facilitate independence and avoid more expensive institutionalization in the future.


The primary focus when helping TBI pain patients should involve understanding the diagnoses, recognizing pain, assisting with pain relief and providing the opportunity to improve function. This is accomplished by evaluating physical, cognitive and psychosocial functioning. If this comprehensive approach is overlooked, then the patient’s pain and function have not been truly managed. n

Several previous studies have evaluated daily opioids for severe chronic daily headache.20,21,24 While success rates have been relatively low, they represent patients who have failed the usual ministrations, and who have few options available.

The advantages of long-acting opioids include:

  • avoidance of the “end-of-the-dose” phenomenon, with mini-withdrawals throughout the day
  • consistent dosing one or two times daily, which decreases the obsession with the next dose
  • maintenance of stable blood levels
  • avoidance of acetaminophen, aspirin and NSAIDs that are included in many short-acting preparations
  • probable diminished risk of significant abuse
  • better compliance, with less psychological dependency on the drug

Disadvantages of long-acting opioids include:

  • social stigma
  • fatigue and constipation
  • difficulty in obtaining scripts, with no refills available
  • need for frequent office visits and monitoring
  • risk of opioid-induced hyperalgesia
  • risk of abuse, although probably less than the SAOs
  • interactions with other sedating drugs and alcohol
  • risk of overdose

Opioid Abuse

Opioid abuse is much more common than true addiction. In general, using opioids for therapeutic reasons other than pain constitutes abuse. In a headache practice, the most common reasons for abuse are using the opioids to alleviate moods, anxiety or depression.

Patients in our previous study were assessed for behaviors typical of opioid abuse or overuse. The criteria that we used included: early refill requests, dose escalations, insistence on increasing doses, abusive treatment of the staff regarding refills, false reports of stolen or lost medications, utilizing the opioid for depression or anxiety, using the opioid for other pains not discussed with the physician, receiving similar medication from other physicians, unexpected or abnormal urine screening test results, using illicit drugs or alcohol, missing, canceling, or refusing appointments, selling the drugs, obtaining opioids from non-medical arenas, frequent ER visits for opioids, hoarding, forging or altering scripts, borrowing or stealing similar medications from family and friends, physical signs of overuse or addiction, and calls to the physician from family members with concerns about patient overuse.25,26

There is a range of abuse, from the person who samples his spouse’s codeine prescription once in a while to the addict who obtains hundreds of opioid tabs from the internet. We cannot paint all abusers with one broad brush. Some situations need watching, such as the patient who took her mom’s pills because she had excess pain; this behavior is a red flag and the patient may be an abuser. For a different patient, one who has already been prescribed low dose, long-acting morphine, the discovery of undisclosed opioid prescriptions from other sources must be regarded as severe abuse; in this situation, discontinuation of the opioids is necessary.

It is not always clear how serious the abuse is. Minor aberrant behaviors are often overlooked. It is not as if any one aberrant behavior warrants immediate discontinuation of an opioid, but most of the serious overuse situations have previously had a number of minor abuse occurrences. Physicians must pay attention to red flags, particularly those that arise early in the relationship with the patient. In my experience, pain patients who raise objections to urine tests usually have a drug problem. Specimen collections should be random and not scheduled. Urine testing serves two purposes : one is to identify other substances that are present but should not be. Another is to measure the levels of the prescribed substance for compliance. When there is no opioid present, there is sometimes a lab error or test insensitivity, but it may be that the patient has been binging early on and has run out of drugs before the visit.27 Another possibility is that the patient is selling the drugs.

In those who self-medicate, a drug is used for a purpose other than the intended one, such as using an opioid as a mood stabilizer or enhancer. Opioids can be both calming and stimulating, often giving a brief burst of energy followed by a tranquil period. Chemical coping is all too common, but is poorly understood and under-researched.28 All addicts are chemical copers to some degree, but not all people who cope chemically are addicts. The person who utilizes one or two pills of hydrocodone a day for stress and anxiety is not an addict by definition, but is certainly using chemicals to cope. The severe patients basically live for the drug; their lives are controlled by procurement of the drug, and they have few coping skills outside of using the drug.29 They will self-escalate their drug use, particularly during periods of high stress.

As much as 35% of patients with chronic pain may fall under the definition of chemical copers.30 There are gender differences, with women using the substances primarily for anxiety, stress and depression. Women are at somewhat of an increased risk for chemically coping than are men.29 Men may utilize the drugs for anxiety and depression, but also use them out of boredom, particularly when they are disabled by their pain. For some men, there is a strong relationship between substance abuse and sensation seeking.29

While physical dependence and tolerance are to be expected with long-term opioid use, addiction is not. Addiction constitutes a biologic and behavioral disease. Most abusers can stop using the drug when harm occurs, but an addict cannot. Whether a patient with previous addictions should be treated with long-acting opioids is a complicated issue. It should be approached on a case-by-case basis and is dependent on a number of factors. Among the considerations:

  • What substances were abused?
  • How many years has the patient been clean?
  • Whether the patient successfully completed treatment
  • The quality of the support system
  • Any comorbid psychiatric conditions31
  • Assessment of risk factors

Previous studies have indicated that risk factors for opioid abuse include cigarette smoking, previous drug abuse, a strong family history of drug abuse, stress, young age, early sexual abuse, poor support, low level of functioning due to headache or other pain, pain embellishment, and certain psychiatric conditions.32-34

An NIMH analysis identified certain problems that carried an increased risk for substance abuse. Of those with anxiety, 25% had a substance use problem, as did 33% of those with OCD and 61% in the Bipolar I category. Unipolar depression also carried a higher risk, but not as much as bipolar. Among PD patients, 84% of those with antisocial personality disorders were substance abusers.35 Also, patients with somatization are probably at a higher risk. Untreated ADHD in older adolescent boys carried a 75% risk of substance abuse, while treated ADHD in this category falls to a 25% risk. The boys without ADHD had an 18% overall abuse rate.36 Our study indicated that those with personality disorders were at increased risk for abuse, but that other psychiatric conditions did not lead to more abuse.

Successful Management of Long-acting Opioids

The physician must have knowledge and experience in the use of these drugs. The patient has to be reliable and well known to the practitioner. Many of the problems occur with new patients; it is prudent to wait several visits before prescribing the long-acting opioids—after the physician can establish that there has been little or no previous abuse.

Patients must have demonstrated an adequate response to short-acting opioids. To avoid opioid-induced hyperalgesia, we restrict use to patients who have received SAOs for one year or more. The patient must truly be refractory to the typical ministrations, with multiple adequate trials of the usual preventive medications. Previous abuse of opioids should exclude patients. In this author’s view, previous abuse of SAOs almost always leads to abuse of the LAOs. Pseudoaddiction is certainly encountered, but seems to be rare in headache patients. Be wary of the patient who claims he or she can tolerate almost no medications except for the opioids.

The use of opioids in patients under thirty should be restricted. Younger patients are more likely to develop tolerance; in older patients, particularly after age 65-70, the brain has lost the ability to do the “neuronal gymnastics” necessary in the development of tolerance. Therefore, older patients may remain on the same low dose for a number of years. If a younger patient fulfills all the requirements, such as truly being refractory, is normal psychologically and at low risk for addiction, he or she may be the exception to the age rule. Management of those with chronic migraine involves a biopsychosocial approach. Patients must not rely simply on the drug in order to function. While medications may be a mainstay of therapy, other interventions must be employed. Active coping should be strongly encouraged with each visit, and may involve a variety of approaches. These may include seeing a psychotherapist, physical therapist or other practitioner, or using self-help approaches such as exercise or biofeedback. Passive coping is a major predictor of disability in chronic pain patients. Those patients who rely only on opioids have less chance of sustaining long-term relief. Even though pharmacotherapy is the cornerstone of treatment, it is only part of a more comprehensive plan.

“Management of those with chronic migraine involves a biopsychosocial approach. Patients must not rely simply on the drug in order to function.”

There are three distinct phases in the use of opioids. The first phase is the initiation of treatment. This includes the initial screening and risk assessment, the doctor’s decision as to which opioid to utilize, and the doctor-patient discussion and signing of an opioid agreement. Prior to initiation of LAOs, an assessment of the following should be done: pain level, moods, social and family functioning, work status, physical functioning, and activities of daily living.37

The intermediate phase is comprised of the diligent monitoring of the patient while on the opioid. This must include ongoing assessment of the patient’s pain level and overall functioning, with a watchful eye for signs of abuse. The physical exam on a return visit needs to assess for slurring of words, abnormal gait, and pupillary abnormalities. Do not assume that low risk patients will never abuse the opioids. During the maintenance phase of opioid prescribing, it is remarkable how many seemingly low-risk patients do misuse the drugs.

Patients usually respond fairly quickly to an opioid; if they have not responded by two to four weeks on a low dose, there usually will not be an adequate response.22 If patients do not report an improvement in functioning, or if functioning declines, consideration should be given for withdrawal from the opioid. Some patients have an improvement in pain but a decline in activity, possibly due to sedation or other opioid-related side effects.

The third phase is switching or withdrawing the opioids when abuse has occurred, or there is lack of efficacy. Withdrawing or switching an opioid may be exceedingly difficult in some patients. Each of these phases involves a learning curve on the part of the practitioner and proper documentation by staff members.

In my experience, using higher doses of the opioid rarely works out in the long term. They place the patient at increased risk of addiction and abuse, and complications from withdrawal. It may be thought that, given the great variation in individual responses, the opioid should be increased or “pushed” to whatever level is beneficial. However, medical and regulatory considerations should be limiting factors in keeping the opioid dose at a low level. The choice of opioid may be key; some have been shown to have less abuse potential. The long-acting fentanyl patch is subject to less abuse than oxycodone CR. The once or twice daily, long-acting morphine preparations have not been subjected to widespread abuse.

Methadone may be more effective than some of the other medications, but has a litany of problems associated with it. Besides the social stigma, high protein binding is a risk, which may lead to irregular drug levels, difficulty with withdrawal, and an increased risk for sudden death.38 If methadone is used, it should be started at a very low dose of no more than 5-10mg a day, and titrated slowly. Patients placed on methadone require close monitoring, and other sedatives must be reduced or discontinued. The usual dosing range in my practice is:

  • methadone, 5 to 40mg per day
  • morphine, 20 to 90mg per day
  • oxycodone, 20 to 60mg per day
  • Fentanyl patch, 12.5 to 50mcg per day

Some type of written opioid agreement should be part of the doctor-patient alliance, although there is a lack of evidence that these agreements do much good for the majority of the patients. There is no standard opioid contract; practices should adapt one for their own purposes. There are several resources on opioid agreements, such as the AAPM website, www.painmed.org, the American Pain Society website, www.ampainsoc.org, the Federation of State Medical Boards, Inc., www.fsmb.org, and the US DEA, www.usdoj.gov/dea. In addition there is an excellent article on agreement contracts by Fishman, 1999.39

The treatment of breakthrough pain is controversial. Most of the breakthrough studies have been concerned with cancer pain, where the average number of breakthroughs is 4 per 24 hours.40 For patients with non-cancer breakthrough pain, such as chronic daily headache, I tend to minimize the total opioid and avoid layering pain medicines on top of each other. Prescribing short-acting medications, such as hydrocodone, for chronic headaches greatly increases the abuse rate. The occasional patient can remain on a low dose of the long-acting opioid, with one or two SAOs such as hydrocodone per day, but, in general, try to avoid these SAOs.

Botulinum Toxin Injections (BoNT-A)

Botulinum toxin type A (US trade names: Botox® and Dysport®) has been utilized as a migraine and chronic daily headache preventive since the 1990s.41 The results of studies have varied widely. Two Phase III studies (PREEMPT 1 and 2) with 1,384 CM patients, found Botox useful for improving functioning and reducing disablility. One of the studies was very positive in reducing headache days.42 The preponderance of evidence points to BoNT-A as being safe and efficacious and this author concurs.

There are a number of possible explanations as to why BoNT-A may alleviate pain. One of BoNT-A actions is as an anti-inflammatory at the neuronal level. BoNT-A may block the release of substance P. More importantly, it may also inhibit the level of secretion of calcitonin gene-related peptide (CGRP).41 CGRP has now been recognized as a key inflammatory mediator, a vital cog in the cascade leading to headache. Efforts are underway to develop drugs that are CGRP antagonists. BoNT-A may also block the release of certain other neuropeptides that contribute to the “inflammatory soup.” This neuropeptide blockage, along with BoNT-A inhibitory effects on the excitatory neurotransmitter glutamate, results in a lessening of peripheral sensitization. With the use of BoNT-A, there is also a decrease in central sensitization.43 Relatively few other compounds have an effect on central sensitization, which is so vital to the pathophysiology of chronic migraine.

As with a number of migraine treatments, the results of BoNT-A studies do vary. A number of variables may explain some of the differences, including:41

  • headache severity, chronicity and degree of refractoriness
  • medication overuse
  • patients with differing types of pain (“imploding” vs “exploding”)
  • different methods of assessing outcomes
  • differences in the number of units of BoNT-A used, and the location of injections

In a number of BoNT-A studies, the high placebo response rate has been difficult to overcome in proving efficacy. The optimal mechanics of BoNT-A administration are still a work in progress.44 I usually average 50 units per treatment, but 100 or 200 may be more effective. The injections are most often administered frontally and temporally, with 9 to 12 total injections. There are some patients who do well with as little as 25 units,45 while, at the other end of the range, some outliers respond only to 250 (or more) units.

For some patients, we “chase the pain” and administer additional injections around the area of pain. For those with occipital pain, posterior injections may be very helpful. If patients do not respond to the first treatment, it is worthwhile to repeat BoNT-A at least once more. BoNT-A is expensive but relatively safe. Of course, BoNT-A may be combined with various medication approaches.

Side effects to BoNT-A tend to be minimal; occasionally patients experience a mild droop of one eye. Some have reported numbness or other sensations around the areas of injection. Generalized weakness should not occur with the low doses that are used. On occasion, patients experience an increase in headaches for one to two weeks.

Daily or Frequent Triptans

Some patients respond only to triptan medications (sumatriptan, naratriptan, rizatriptan, almotriptan, zolmitriptan, frovatriptan, eletriptan). Several studies have described the use of daily triptans for the preventive treatment of CDH.46,47

Short-lasting adverse events are often encountered with triptan use. These include paresthesias, fatigue, chest heaviness, jaw or neck discomfort, etc.48 Chest symptoms are, with rare exceptions, not of cardiovascular origin. Cardiac ischemia due to triptan use is rare.48 Triptans do constrict coronary vessels, but this is a mild and short-lived effect. Despite widespread triptan use, the number of adverse cardiac events has been limited. Echocardiography and electrocardiography generally have been normal after triptan uses, even in the presence of chest symptoms.

The primary issue with frequent triptan use, assuming rebound headache is not present, is long-term adverse events. The cardiovascular system would be the most likely for possible long-term sequelae. Chronic ischemic changes, valvular abnormalities, or fibrosis are theoretical considerations. To date, there is no evidence of long-term triptan use producing any of these adverse events. This has not been systematically studied, however. The number of patients throughout the world who have utilized triptans on a near-daily basis is unknown. Until these patients have been studied, it is reasonable and prudent to do cardiac monitoring, as well as hematologic tests.

The following describes a study that we did on frequent triptan use.46 The patients in this study were never instructed to use triptans on a daily basis. They self-discovered that a dose of triptans would alleviate headache for most or all of the day. Most patients in this study had a long history of headache refractory to usual medications. They finally had found a medication (a triptan) that would alleviate the headache for some time. Most of the patients had been using frequent triptans through their primary care physician. A minority of our patients had increased the amount of triptans prescribed. Patients were withdrawn from triptans in order to determine if rebound headache was present. The only patients who continued on triptans were those who: 1) had been determined to truly be refractory to other approaches, 2) experienced no or minimal side effects, 3) had rebound headaches excluded, and 4) signed a “Frequent Triptan Informed Consent” form. Many patients did not meet these criteria and the triptans were discontinued.

One goal of this retrospective study of a large group of patients was to evaluate the cardiac safety of triptans. A secondary objective was to assess the hematologic tests that were performed in these patients.

For most of the treatment course, most patients (97 of 118) averaged 1 tablet daily (50mg sumatriptan, 2.5mg naratriptan, 10mg rizatriptan, 5mg zolmitriptan). Eight patients used only ½ tablet daily, while 8 others used 1.5 tablets on a daily basis. Five patients consumed 2 tablets daily. Ninety patients used the triptan every day, while 28 patients averaged 4 to 5 days a week. All of the patients would occasionally go for several days without a triptan, or occasionally take a drug holiday for a week or more.

Forty patients had taken a triptan for six months to a year, 37 for two to four years. Forty-one patients had taken daily triptans for 4 or more years: 29 for four to six years, and 12 for more than six years.

The patients were monitored for several years. Routine laboratory (hematologic) tests were done, including complete blood counts and chemistries. No abnormality was felt to be due to the triptans. Electrocardiograms were performed on all of the 118 patients, and no abnormality was determined to be from the triptan. Eight patients did have abnormal electrocardiograms. Echocardiograms (with Doppler) were done on 57/118 patients, and 10 were abnormal. The attending cardiologist did not feel that any of these abnormalities were due to triptan use. Twenty patients underwent stress tests, and all were normal.

Nine patients felt that the triptans contributed to fatigue. Five patients had mild chest tightness at times, possibly due to the triptans; cardiac disease was ruled out. Three patients felt that the triptans contributed to nausea.

Because these patients decided on their own to use triptans on a daily basis, adverse events would be expected to be low. If patients were not tolerating the medication well or were having significant adverse effects, they would not choose to continue the triptan on a frequent basis. There were no adverse consequences from frequent triptan use over a prolonged period.


When prescribed for headache patients, stimulants may be beneficial for various comorbidities, such as attention deficit hyperactivity disorder (ADHD), depression, and fatigue. In addition, stimulants do not cause the weight gain that is seen with a number of other current headache preventives. Amphetamines have been shown to possess intrinsic analgesic properties, primarily through brain catecholamine activity. They also intensify the analgesic effects of certain opioids.49 Stimulants have been utilized to counteract the sedation encountered by opioids. An excellent review article on stimulants as adjuncts for opioids concluded that, “The evidence suggests that amphetamine drugs may enhance the effect of opioids and, at the same time, decrease somnolence and increase cognitive performance.”50

“Amphetamines have been shown to possess intrinsic analgesic properties, primarily through brain catecholamine activity. They also intensify the analgesic effects of certain opioids.”49

As a group, central nervous system (CNS) stimulants cause excitement and euphoria, decrease feelings of fatigue, and increase motor activity.51 Caffeine, the most widely consumed stimulant in the world, is believed to act by several mechanisms of action in the pre-frontal cortex and other areas of the brain. These include translocation of extracellular calcium, inhibition of phosphodiesterase, and adenosine receptor antagonism, resulting in decreased fatigue and increased mental alertness.51

Nicotine, the active ingredient in tobacco, specifically stimulates nicotinic receptors in the autonomic ganglia, resulting in euphoria, arousal, relaxation, and improved attention, learning, problem solving, and reaction time.51 However, in very high doses, nicotine causes blockade of autonomic ganglia, resulting in respiratory depression and severe hypotension.

Amphetamine and its derivatives, such as methylphenidate, demonstrate indirect CNS and PNS effects similar to cocaine. Like cocaine, they initially increase levels of catecholamines. However, amphetamines do this by a different mechanism of action. They accomplish this effect by causing the release of intracellular stores of catecholamines and inhibiting monamine oxidase (MAO).51 The major cause of the behavioral effects of amphetamines is thought to be due more to release of dopamine rather than norepinephrine.51 This ultimately results in increased alertness, decreased fatigue, decreased appetite, and insomnia as well as the usual “fight or flight” response characteristic of adrenergic stimulation in the PNS.

Amphetamines have been known to possess independent analgesic activity, possibly due to release of norepinephrine. The effect was felt to be about the same as that of ibuprofen. Also, stimulants may potentiate the analgesic actions of opioids.50 The most commonly studied combination has been dextroamphetamine and morphine. Methylphenidate has also been studied as an opioid adjunctive medication. In one small study, the use of dextroamphetamine for patients with tension and migraine headache was assessed. It concluded that dextroamphetamine was viable as a preventive medication for chronic tension and migraine headaches in some subjects.52 In another case report, a man was successfully treated with methylphenidate for his refractory episodic cluster headaches.53

One of our previous studies assessed 73 chronic migraineurs who had been prescribed stimulants in addition to their other medications. While the stimulants were primarily prescribed for certain comorbidities, their effect on headaches was also assessed. Seventy-five percent of the patients who were placed on the stimulants remained on them for at least 9 months. Thirty-four percent of the 73 patients both remained on the stimulants and reported positive efficacy with regard to headache. Forty-one percent of the patients suffered at least one adverse event, while only two patients abused the stimulant.54

Table 4. Sunnybrook Health Center MAOI Diet57
Food Group Food to Avoid Food Allowed
Cheese Mature or aged cheese, casseroles made with these cheeses; all others except listed in ‘allowed’ column Fresh cottage, cream, and ricotta cheese and processed cheese slices; all fresh milk products
Meat, fish, poultry Fermented/dry sausage, pepperoni, salami, mortadella, improperly stored meat, fish or poultry All fresh packaged or processed meat, fish or poultry; stored in refrigerator and eaten as soon as as possible
Fruits and vegetables Fava or broad bean pods, banana peel Banana pulp, all others except listed in ‘avoid’ column
All tap beer Alcohol: no more than
2 domestic or canned beers
or 4 oz. wine a day
Miscellaneous foods Marmite yeast concentrate, sauerkraut, soy sauce and soy condiments Other yeast extracts, soy milk

Stimulants have proven utility for certain conditions, such as ADHD. For patients with these comorbidities the stimulants may also be beneficial for a minority of patients with chronic migraine.

Advantages of stimulants include enhanced cognition and alertness, with no weight gain. Disadvantages primarily revolve around the side effects, such as anxiety or insomnia. Abuse may certainly occur, but it is uncommon in adults. Stimulants should be considered in patients with certain comorbidities. The few studies to date have indicated a positive role for stimulants, but further studies on stimulants for headache would help to clarify that role.

Monoamine Oxidase Inhibitors (MAOIs)

For those with RCM and unipolar depression, MAOIs may be of help. MAOIs are sometimes effective for treatment-resistant depression.55 They are also effective for alleviating anxiety. MAOIs were commonly prescribed in the 1980s, but with the advent of SSRIs and triptans, they fell out of favor. The available literature on MAOIs for headache treatment dates to the 1970s and 80s. For a select group of RCM patients, the MAOIs greatly enhance quality of life. At this point, I believe that MAOIs are under-utilized.

The traditional, classical MAOIs form an irreversible complex with the enzyme monamine oxidase. Monamine oxidase is located in a number of tissues, including the brain. The mechanism of action is most likely receptor-mediated pre- and post-synaptic events, not simply an increase in serotonin.55 Phenelzine, a traditional MAOI, has been the one most commonly used for headache.

One non-traditional reversible MAOI is moclobemide, which is not available in the USA. Moclobemide has fewer dietary and medication restriction than the classic MAOIs. The transdermal selegiline patch is a selective MAO-B inhibitor that does not require the tyramine-restricted diet. The efficacy of these non-traditional MAOIs is not as clearly established as the more traditional MAOIs (phenelzine).56

Careful patient selection is crucial when using the MAOIs. Patients need to carefully observe the restrictions on diet and medications. I usually prescribe low doses of phenelzine, 15mg tablets, and start with one tablet at night, increasing after one week to two at night. If no response is noted after three to four weeks, I usually push the dose to 3 tablets at night. By always using the MAOI at night, the patient is less likely to encounter a food interaction. Five tablets a day (75mg) is the usual maximum. Side effects include insomnia, weight gain, sedation, and orthostatic hypotension. The MAOIs have a reputation as being somewhat dangerous and difficult to use. Despite this reputation, MAOIs are usually well-tolerated.

The previous MAOI diets were overly restrictive. The listed risk of most foods was based on anecdotal cases. Newer evidence-based diets are easier to follow. See Table 4 for the MAOI diet.

The hypertensive crisis that may occur with a food interaction is due to a number of factors, primarily the amount of tyramine absorbed into the bloodstream. The tyramine content of food has been difficult to accurately establish. When patients consume the phenelzine at night, in low doses, while avoiding the major tyramine-rich foods, interactions are less likely. The reversible MAOI moclobemide is much less likely to trigger any adverse reaction.

The serotonin syndrome may occur due to the administration of serotonergic drugs and MAOIs. SSRIs should not be concurrently used. Other drugs that should be avoided include amphetamines, sympathomimetics, pseudoephedrine, certain opioids (meperidine), dextromethorphan, and others. Most triptans are not utilized with MAOIs, but low doses of frovatriptan may be used with caution.

For those patients suffering from both refractory chronic headache and treatment-resistant depression, MAOIs may offer some measure of hope. They also alleviate anxiety. When cautiously used, the MAOIs are not as dangerous as their reputation might imply.


Refractory chronic migraine is often a disabling and debilitating illness. We face major challenges in attempting to define RCM. The definition must allow for severity of illness; also, degrees of refractoriness may change over time.

Other major areas of study within RCM include pathophysiologic mechanisms, the role of medication overuse, search for biomarkers, psychological comorbidities, non-medication approaches, and pharm-acotherapy.

Patients with RCM who have medication overuse headache or psychological comorbidities require a combination of approaches. It “takes a village” to help those with severe, refractory headaches, and we need to guide the patient into comprehensive treatments. There are a number of viable therapeutic approaches, five of which are presented in this article. However, we desperately need breakthrough medications and technologies that can prevent headache pain.


Dr. Robbins is a partner in Brain Stimulation Chicago North Shore, which provides TMS therapy for depression.

Last updated on: October 25, 2012
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